The zipper model of translational control: a small upstream ORF is the switch that controls structural remodeling of an mRNA leader

Cell. 2003 May 16;113(4):519-31. doi: 10.1016/s0092-8674(03)00345-3.


Transport of the essential amino acids arginine and lysine is critical for the survival of mammalian cells. The adaptive response to nutritional stress involves increased translation of the arginine/lysine transporter (cat-1) mRNA via an internal ribosome entry site (IRES) within the mRNA leader. Induction of cat-1 IRES activity requires both translation of a small upstream open reading frame (uORF) within the IRES and phosphorylation of the translation initiation factor eIF2alpha. We show here that translation of the upstream ORF unfolds an inhibitory structure in the mRNA leader, eliciting a conformational change that yields an active IRES. The IRES, whose activity is induced by amino acid starvation, is created by RNA-RNA interactions between the 5' end of the leader and downstream sequences. This study suggests that the structure of the IRES is dynamic and regulation of this RNA structure is a mechanism of translational control.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 5' Untranslated Regions / genetics
  • 5' Untranslated Regions / metabolism*
  • Animals
  • Arginine / deficiency*
  • Base Sequence / genetics
  • Cationic Amino Acid Transporter 1 / genetics
  • Cationic Amino Acid Transporter 1 / metabolism*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Eukaryotic Cells / cytology
  • Eukaryotic Cells / metabolism*
  • Eukaryotic Initiation Factors / genetics
  • Eukaryotic Initiation Factors / metabolism*
  • Lysine / deficiency*
  • Models, Biological
  • Molecular Sequence Data
  • Molecular Structure
  • Open Reading Frames / genetics*
  • Phosphorylation
  • Protein Biosynthesis / genetics
  • Rats
  • Ribosomes / genetics
  • Ribosomes / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Tumor Cells, Cultured


  • 5' Untranslated Regions
  • Cationic Amino Acid Transporter 1
  • DNA-Binding Proteins
  • Eukaryotic Initiation Factors
  • Transcription Factors
  • Arginine
  • Lysine